To improve my chemistry, i revisit some synthetic route seen in literature, only on paper with a small bibliographic study to check the feasibility of some hypothesis, with chemical and process optimization for industrialization.
In the search field below, type a reactions class (ex: alkylation) or name (ex: Lossen rearrangement) to find the message containing the link to the report which use the desired reaction. Also, references are clickable in reports.

Sunday, November 8, 2015

Alternate route proposal for VX-970 an ATR inhibitor (for fun only)

Target

Presentation

The original route published by Vertex begins with the already synthesised pyrazine core (9 to 12 steps depending if the boronic acid is bought or synthesised) with 2 metal catalyzed cross-coupling. This route is obviously the shorter access to the target, but suffers of two drawbacks which are inevitable:
- 2 Pd Cross-coupling which sometimes could be capricious under scale up
- Use of boronic derivative recognized now as mutagen.

Considering these facts, i have chosen to first optimize the original route (process only) except the 2 cross-coupling, and secondly to propose an alternate route which avoids cross-coupling reactions with the construction of the Pyrazine core, which is very prospective.

This is a good chemistry exercise only, since the stability of intermediates is unknown, especially at the end of the synthesis starting at part III, and there are a larger number of steps, but i have some fun chemically speaking, even if this route is less efficient.

Also, it could give some ideas, which is the second role of this blog, like:

In-situe oxidation of KCN to N2 as post-reaction treatment (inspired from mining industry) – part II

Oxone® as friendly oxidizing reagent for various oxidations types – part IV

Friedel & Craft on Zeolite (avoiding the use of AlCl3) – part I and II

Possible replacement of “wet-alumina” which needs a preparation by pseudo-Boehmite – part II

About Zeolite, i think this is a catalyst of choice for the flow chemistry (zeolite cartridge).

This proposal is divided in four parts because this is a very long report with nearly 20-21 steps (there are more than 20 chemicals transformations, but by using minerals reagents in many cases, and expected 9 isolations), and multiple proposals for the first step of the sulfonyloxime (19) synthesis, considering starting material prices and chemistry:

Disclaimer:This is some personal works on paper only, i
have no responsibility in any way if somebody would try this route and
has all sort of troubles, including but not limited to: injuries and
money loss. This is for experienced chemists only, and tests must be
conducted in a suitable lab only.

But if my work is
used to synthesize the targeted molecule described here, please, send a
word, even if it fails, chemistry is always an experimental science.
This will make me pleased, thank you.